Hornung Lab - Research

The Inflammasomes

Inflammasomes constitute a family of cytosolic sensors that can directly detect microbial molecules but also indirectly sense damage by detecting the perturbation of cellular homeostasis. Within recent years a lot of progress has been made in the characterization of inflammasome components and their pivotal role as surveillance machineries in the context of infection. Besides, it has become evident that many non-communicable diseases are triggered or perpetuated by inflammasomes and several studies have uncovered the great therapeutic potential of targeting these pathways. In that respect, inflammasomes have also become a prime focus for the development of novel anti-inflammatory therapies.

The minimal inflammasome signaling unit consists of a sensor protein and pro-caspase-1 that gets recruited to this sensor upon activation. Most inflammasomes, however, make use of the additional adapter protein ASC that serves to introduce a threshold-like signaling behavior and to amplify the response. The sensor protein itself often encodes for an oligomerization function that is engaged upon activation. This oligomerization of the sensor serves to form a seed-like structure that is required to initiate the assembly of a filamentous signal hub by the adapter protein ASC, which in turn recruits pro-caspase-1. In the case of NLR (nucleotide-binding domain and leucine-rich repeat-containing) proteins, it is the central NACHT domain that serves this function. Upon recruitment to the inflammasome complex, pro-caspase-1 is activated so that it can mature its substrates, such as the highly pro-inflammatory cytokine pro-IL-1β. Furthermore, caspase-1 cleaves the pore-forming molecule GSDMD, which triggers the lytic cell death of pyroptosis.

Next to its prominent role in processing of proinflammatory cytokine targets, caspase-1 also cleaves many other cytosolic proteins, the role of those is only starting to be understood. In our current projects we are mainly focusing on two inflammasome complexes: on the one hand, AIM2, a very specific sensor for cytosolic DNA and on the other hand NLRP3, a very important, yet up to now mechanistically poorly understood NLR sensor that responds to a large variety of cytoplasmic damage signals.

Using various complementary approaches, we are currently trying to understand their molecular mechanisms of activation and we aim at deciphering their functional roles at the cellular and organismic level in health and disease.

 

Recent publications in this area:

IKKβ primes inflammasome formation by recruiting NLRP3 to the trans-Golgi network.
Schmacke NA, O'Duill F, Gaidt MM, Szymanska I, Kamper JM, Schmid-Burgk JL, Mädler SC, Mackens-Kiani T, Kozaki T, Chauhan D, Nagl D, Stafford CA, Harz H, Fröhlich AL, Pinci F, Ginhoux F, Beckmann R, Mann M, Leonhardt H, Hornung V.
Immunity. 2022 Dec 13;55(12):2271-2284.e7. doi: 10.1016/j.immuni.2022.10.021. Pubmed

ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome.
Robinson KS, Toh GA, Rozario P, Chua R, Bauernfried S, Sun Z, Firdaus MJ, Bayat S, Nadkarni R, Poh ZS, Tham KC, Harapas CR, Lim CK, Chu W, Tay CWS, Tan KY, Zhao T, Bonnard C, Sobota R, Connolly JE, Common J, Masters SL, Chen KW, Ho L, Wu B, Hornung V, Zhong FL.
Science. 2022 Jul 15;377(6603):328-335. doi: 10.1126/science.abl6324. Pubmed

Post-injury immunosuppression and secondary infections are caused by an AIM2 inflammasome-driven signaling cascade.
Roth S, Cao J, Singh V, Tiedt S, Hundeshagen G, Li T, Boehme JD, Chauhan D, Zhu J, Ricci A, Gorka O, Asare Y, Yang J, Lopez MS, Rehberg M, Bruder D, Zhang S, Groß O, Dichgans M, Hornung V, Liesz A.
Immunity. 2021 Mar 1. doi: 10.1016/j.immuni.2021.02.004. Pubmed

Human NLRP1 is a sensor for double-stranded RNA.
Bauernfried S, Scherr MJ, Pichlmair A, Duderstadt KE, Hornung V.
Science. 2020 Nov 26:eabd0811. doi: 10.1126/science.abd0811. Pubmed

CARD8 inflammasome activation triggers pyroptosis in human T cells.
Linder A, Bauernfried S, Cheng Y, Albanese M, Jung C, Keppler OT, Hornung V.
EMBO J. 2020 Aug 25:e105071. doi: 10.15252/embj.2020105071. PubMed

Inflammasome-Dependent Induction of Adaptive NK Cell Memory.
van den Boorn JG, Jakobs C, Hagen C, Renn M, Luiten RM, Melief CJ, Tüting T, Garbi N, Hartmann G, Hornung V.
Immunity. 2016 Jun 21;44(6):1406-21. doi: 10.1016/j.immuni.2016.05.008. PubMed

Human Monocytes Engage an Alternative Inflammasome Pathway.
Gaidt MM, Ebert TS, Chauhan D, Schmidt T, Schmid-Burgk JL, Rapino F, Robertson AA, Cooper MA, Graf T, Hornung V.
Immunity. 2016 Apr 19;44(4):833-46. doi: 10.1016/j.immuni.2016.01.012. PubMed

A Genome-wide CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) Screen Identifies NEK7 as an Essential Component of NLRP3 Inflammasome Activation.
Schmid-Burgk JL, Chauhan D, Schmidt T, Ebert TS, Reinhardt J, Endl E, Hornung V.
J Biol Chem. 2016 Jan 1;291(1):103-9. doi: 10.1074/jbc.C115.700492. PubMed

 

Selected reviews in this area:

The NLRP3 inflammasome renders cell death pro-inflammatory.
Gaidt MM, Hornung V.
J Mol Biol. 2017 Dec 1. pii: S0022-2836(17)30563-6. doi: 10.1016/j.jmb.2017.11.013. [Epub ahead of print] Review. PubMed

Alternative inflammasome activation enables IL-1β release from living cells.
Gaidt MM, Hornung V.
Curr Opin Immunol. 2017 Feb;44:7-13. doi: 10.1016/j.coi.2016.10.007. Epub 2016 Nov 11. Review. PubMed 

Pore formation by GSDMD is the effector mechanism of pyroptosis.
Gaidt MM, Hornung V.
EMBO J. 2016 Oct 17;35(20):2167-2169. Epub 2016 Aug 29. No abstract available. PubMed